The capacity of -cells to expand in response to insulin resistance is critical to develop type-2 diabetes and -cell proliferation is a major component for these adaptive responses. The long-term goal of our previous and proposed studies under this award is the understanding of the molecular mechanisms that regulate -cell mass with emphasis in proliferation. During the current funding period, we focused on the mechanisms by which Akt and the tuberous sclerosis complex 2 (TSC2) regulate -cell mass and cell cycle progression. These studies identified the TSC2 and the mTOR/raptor complex (mTORC1) as important molecules regulating -cell mass and proliferation. mTORC1 controls growth and proliferation by activation of 4E-BP and S6 kinases (S6K). Moreover, mTORC1 also mediates a negative feedback loop to attenuate Akt signaling. However, uncertainty remains as to the underlying mechanism and key downstream effectors responsible for controlled -cell expansion by mTORC1. The objective of this application is to understand how mTORC1 targets regulate -cell mass and proliferation. We hypothesize that -cell mass expansion by mTORC1 signaling is mediated by a balance between two processes: activation of downstream targets and negative feedback inhibition of IRS/Akt signaling. The specific aims are (1) to establish how mTORC1 targets regulate -cell mass expansion. These studies will evaluate the individual contributions of S6K1 and 4E-BP on regulation of cell growth and proliferation. (2) Determine how decreased Akt signaling by mTORC1-mediated negative feedback modulates -cell mass expansion. These experiments will evaluate the role of GSK3 and FoxO on mTORC1-S6K mediated feedback inhibition on IRS/Akt signaling. This proposal will provide important insights into the molecular mechanisms that govern -cell mass expansion by mTORC1. This information can be used to expand drug development opportunities for diabetes. PUBLIC HEALTH RELEVANCE: Failure of -cells to expand or adapt to insulin resistance results in type 2 diabetes. The current evidence support the concept that mTORC1 is active in states of increased insulin demand and plays a major role in - cell adaptation to insulin resistance The goal of this application is to unravel how mTORC1 regulates -cell mass in an effort to develop strategies to identify pharmacological targets to improve -cell mass and function for the treatment of diabetes.